Organic Synthesis II: Selectivity & Control

8 lectures, TT 2011
Dr Martin Smith
Ofce: CRL 1
st
foor 30.087
Telephone: (2) 85103
Email: martin.smith@chem.ox.ac.uk
Handout 1
Handouts will be available at:
http://msmith.chem.ox.ac.uk/teaching.html
HN
MeO
H
O
! Organic Synthesis II: Selectivity & Control. Handout 1
! Selectivity and Control
! Definitions: Chemo- and Regio-selectivity
! Recap of selective reactions: reductive amination
1,4 vs 1,2 addition
Electrophilic aromatic substitution
Nucleophilic aromatic substitution
! Stereoselectivity: definitions and recap
! Selectivity and disconnection
! The finished product: total synthesis of (+-) methyl homosecodaphniphyllate
! Chemo- and Regio-selectivity in oxidation of alcohols
! Oxidation as a common functional group interconversion
! Oxidation of alcohols: Cr(VI) oxidants
! Activated DMSO oxidants: Swern, Moffatt and Parikh-Doering procedures
! Application to the generation of bis-aldehydes : (+-) methyl homosecodaphniphyllate
! Hypervalent iodine: Dess-Martin periodinane
! MnO
2
and Oppenauer Oxidations
! Catalytic Oxidants: TPAP and TEMPO
! Chemo- and Regio-selectivity in reduction of carbonyl derivatives
! Selectivity in DIBALH reductions: stopping reactions half-way
! Selectivity in (general) hydride reductions
! Using amides as electrophiles: Weinreb amides and examples; the problem of C-acylation
! An aside: acylation at carbon - kinetic and thermodynamic control
! Kinetic control: use of methylcyanoformate
! Selectivity in hydride reducing agents: Lithium Aluminium Hydride
Lithium Borohydride
Borane (and related complexes)
NaBH
4
; modified borohydrides & the Luche reduction
! Organic Synthesis II: Selectivity & Control. Handout 1
!Stereoselectivity in hydride reductions:
1,2 stereoinduction (Felkin models and variants)
1,3 stereoinduction (1,3-syn and 1,3-anti diols
Additions to cyclohexanones (torsional control)
Enantioselectivity in hydride reduction
A catalytic asymmetric hydride reduction
! Recap: reduction of alkynes
! Dissolving metal reductions: the Birch reduction
! Dissolving metal reductions of !,"-unsaturated ketones (and esters)
! Hydrogenation
! Oxidation reactions involving alkenes
! Recap: dihydroxylation and allylic alcohol reactions
! Osmium-mediated hydroxylation
! Allylic alcohol mediated alkene functionalization
! Titanium mediated epoxidation: the Sharpless Epoxidation
! The Wacker oxidation
! Epoxidation vs Baeyer-Villiger
! Nucleophilic epoxidation of electron deficient alkenes
! Books & other resources: 1. Oxidation & Reduction in Organic Synthesis (T. J. Donohoe, OUP)
2. Organic Chemistry (Clayden, Greene, Wothers & Warren, OUP)
3. Professor Andrew Myers website (Harvard).
http://www.chem.harvard.edu/groups/myers/page8/page8.html
4. Molecular Orbitals and Organic Chemical Reactions
(I. Fleming, Wiley, 2nd Edn.)
Mechanisms for many oxidation reactions (even well-known ones) are significantly more complex
than drawn throughout this course (and in many cases are not known or understood). Some are
based on factual mechanistic data; some should be treated more as a mnemonic than explanation.
! Chemo-selectivity
Selectivity between two functional groups
! Regio-selectivity
Selectivity between different aspects of the same functional group
with nucleophiles
or reducing agents
reaction with
peroxy-acids
Which
group
reacts?
! What is Selectivity & Control? (and why do we need it?)
O O
OMe
O
O
X
direct or conjugate
addition with nucleophiles
or reducing agents
ortho-, para- or meta-
with electrophiles
and selectivity
between o- and p-
Where
does it
react?
! Chemoselectivity: reactions you have already seen
! Functional groups have different kinds of reactivity
O OH O
Pd/C
H
2
NaBH
4
! Functional groups have similar reactivity
OMe
O O
OMe
OH O
OH
O
NaBH
4
use nucleophilic
reagent
ketone-
electrophilic
alkene- not
electrophilic
C=C weaker #-
bond than C=O
use catalytic
hydrogenation
ketone- more
electrophilic
ester- less
electrophilic
use selective
reagent
protect more
reactive group
! Chemoselectivity: reactions you have already seen
! Functional group may react twice (is the product more reactive than the SM?)
Chemoselectivity needed between Starting Material and Product
R
1
NH
2
R
1
N
H
R
2
R
1
N R
2
R
2
Br R
2
Br R
2
control?
R
1
NH
2
O R
2
H
R
1
N R
2
H
R
1
N
H
R
2
or H
2
, Pd/C
NaB(CN)H
3
! Solution: use reductive amination (more on reduction later)
Chemoselectivity: NaBH
3
CN only reduces imine, not aldehyde starting material
[NaBH
3
CN is a less nucleophilic source of hydride than NaBH
4
due to the
electron-withdrawing nature of the cyanide ligand. As a consequence it will
generally not reduce aldehydes and ketones at neutral pH]
! Regioselectivity: reactions you have already seen
! Conjugate and Direct Addition to Enones
! Electrophilic Aromatic substitution
X X
E
X X
E
E
E
E
and/or
O OH
Nu
O Nu
Nu
Nu
Direct
Conjugate
[Michael]
the enone is electrophilic
at two different sites
kinetic product
hard nucleophiles
thermodynamic product
soft nucleophiles
choose 'ortho, para-'directing
group X: Alk, OH, F etc
choose 'meta-
'directing group X
COR, NO
2
etc
! Stereo-selectivity
Selectivity between two (or more!) possible stereochemical outcomes
Examples youve already seen: (I) reduction of cyclohexanones (see course from Dr E. Anderson, HT 2011)
Examples youve already seen: (II) Additions to chiral aldehydes & ketones (Felkin-Anh model)
! What is Selectivity & Control ? (and why do we need it?)
H
t
Bu
O
H
t
Bu
H
OH
H
t
Bu
OH
H
'Hydride'
Which face
is attacked?
equatorial
attack
axial
attack
"H
-
"
"H
-
"
R
S
R
M
R
L
O
H Nu
1. Reactive conformation
2. Brgi-Dunitz trajectory
3. Attack away from R
L
and over R
S
4. TS is SM-like
Ph
Me
O
Me
Ph
Me
OH
Me
LiBH(s-Bu)
3
[bulky hydride]
! Disconnections that require selectivity: simple aromatic derivatives
! Selectivity defines strategy in disconnection
Dinocap - fungicide
Order is important (the alternative C-N disconnection prior to the C-C disconnection
would not lead to appropriate selectivity)
! Reminder of basic principles: where and when to disconnect?
(i) branch points (ii) heteroatoms (iii) functional groups
(iv) simplifying transformations (v) the order of events
(see 1st year course from Prof Gouverneur)
O
2
N NO
2
O
O
O
2
N NO
2
OH
O
2
N NO
2
OH OH
C-O
C-C
C-N
directs ortho-
for C-C bond
formation
para- position
blocked
directs ortho-
and para- for
nitration
Esterification
Friedel
Crafts
(issues?)
Nitration
! Two group disconnections: Fluconazole
! Selectivity defines strategy in disconnection
! The 1,2 difunctional disconnection
1
2 2
F
F
N
N
N
F
N
N
N
N
N
N
F
OH O
NH
N
N
F
F
N
N
N
O
1
2
F
F
Cl
O
NH
N
N
F
F
Cl
Cl
O
1,2 di-X
C-N
sulfur
ylid
C-N
1,2 di-X
C-C
Friedel
Crafts
least hindered
end attacked
F is o-, p-
directing
Deactivating: only
monoacylation
R
2
N
OH
RS
OH
HO
OH
X
OH
1,2 di-X
OH + X
-
! Complex molecule synthesis
! We need to exert control to be able to construct complex molecules efficiently
! Selectivity - as defined by disconnection - offers an opportunity to do this
HN
CO
2
Me
H
Methyl homoseco-
daphniphyllate
! Isolated from the bark of Daphiphyllum macropodum
! Structure confirmed by X-ray crystallography
! Complex architecture contains five fused rings
! Selectivity defines strategy in disconnection
! Starting at the end: the same disconnections work regardless of complexity
R =
Methyl
homosecodaphniphyllate
OBn
H
N
H
N
BnO
H
H
N
BnO
H
H
HN
MeO
2
C
H
redrawn
OBn
H
O
O
OBn
H
O
N
MeO
2
C
R
OBn
O
N
MeO
2
C
R I
R
R
1
FGI (ox)
Diels
Alder
1,1 C-X
(Prins)
2 x C-N
imine
formation
FGI (ox)
C-C
(1,4 addition)
C-C
(enolate
alkyation)
2 x C-C
! Synthesis of (+/-) methyl homosecodaphniphyllate (I)
! An elegant, selective and controlled approach:
Heathcock et al., J. Am. Chem. Soc., 1988, 10, 8734
Generate lithium
enolate
Regioselective
1,4 addition
S
N
2 alkylation
[on carbon, not
oxygen]
Chemoselective
reduction (ester vs
amide)
Amide hydrolysis
and lactonization
1. LDA
O
MeO
I
N
O
OBn
H
N
O
OBn
H
HO
N
O
OBn
MeO
2
C
H
OMe
LiO
N
OLi
DIBALH
OBn
H
O
O
1. KOH, 95C
2. H+
OBn
Amide gives
predominantly Z enolate
N
O
OBn
H
! Synthesis of (+/-) methyl homosecodaphniphyllate (II)
! An elegant, selective and controlled approach:
OBn
H
O
O
1.LiAlH
4
OBn
H
HO
HO
OBn
H
O
O
(COCl)
2
, DMSO
Et
3
N, CH
2
Cl
2
OBn
H
HN
OBn
H
N
O
NH
3
NH
3
OBn
H
N
H
AcOH
Chemoselective
reduction of
lactone to diol
Swern Oxidation
Chemoselective
oxidation to
bis-aldehyde
Imine formation
Enamine
formation
N-protonation
! Synthesis of (+/-) methyl homosecodaphniphyllate (III)
! An elegant, selective and controlled approach:
OBn
H
N
H
AcOH, 75C
N
BnO
H
H
redrawn as:
N
BnO
H
H
N
AcOH, 25C
!4s + !2s
H
HN
BnO
H
HN
BnO
H
-H
+
!4s
!2s
Prins reaction
Electron rich alkene
traps electron poor iminium
cation (to give a tertiary
carbocation)
Regioselective and
Chemoselective
intramolecular Diels
Alder reaction
! Synthesis of (+/-) methyl homosecodaphniphyllate (IV)
! Final steps:
! A series of simple but selective steps
! Chemo-selectivity, regio-selectivity (and stereoselectivity) are
exploited throughout the synthesis to great effect.
! Overall: nine steps - a spectacularly elegant and efficient approach
We will cover the details of many of these steps throughout the course
HN
BnO
H
HN
HO
H
HN
CO
2
Me
H
H
2
, Pd-C
1. CrO
3
, H
2
SO
4
,
H
2
O, Acetone
2. MeOH, H
+
Removes benzyl
protecting group
and reduces alkene
Chemoselective
oxidation to acid;
Esterification
! Oxidation is a very common synthetic transformation
! Many functional group transformations are redox reactions
Oxidation = Electrophilic attack = Removal of electrons
! Common 2-electron transformations:
Br Br Br
Br
Br
Br
S
N
2
inversion
Base
-2HBr
bromonium
cation
dibromide product
elimination electrophilic attack
Enters as Br
+
Leaves as Br
-
2 electron oxidation
So functional groups that react readily with electrophiles are easily oxidized
This includes: alcohols, alkenes, amines and phenols
-2e -2e
-2e -2e
R OH R
O
R OH
O
alcohol aldehyde acid
R NH
2
R NH
R
amine imine nitrile
NH
! Selectivity in oxidation of alcohols
! Reagents youve seen: Cr(VI) oxidation to generate ketones (idealized mech.)
! Selective oxidation is a challenging transformation
Cr(IV)
Generally use Cr(VI), Mn(VII), high oxidation state Sulfur or Iodine
Problems: aldehydes are reactive so over-oxidation can be a problem - avoid water!
[ox]
+H
2
O
-H
2
O
[ox]
aldehyde hydrate acid primary alcohol
R OH R
O
R OH
OH
R OH
O
Cr(VI)
OH
Cr
O
O O
O
Cr
OH
O
O
H
RDS
Chromate Ester
O
! Selectivity: variants of chromium oxidants
! Common Cr reagents:
PDC in dry DCM works
well for 1 alcohol to
aldehyde oxidation. In
DMF oxidation to acids
occurs
Oxidizes 1 alcohols to
carboxylic acids; 2 alcohols
to ketones. Not suitable for
acid sensitive substrates
PCC will oxidize 2
alcohols to ketones
and 1 alcohols to
aldehydes (if kept dry!)
Selective oxidation can be problematic with these reagents & stoichiometric chromium
can create waste disposal problems - so many alternatives.
H
2
Cr
2
O
7
Jones reagent
Chromic acid in H
2
SO
4
Usually acetone
co-solvent
BnO
OTBS
O
CO
2
Me
BnO CO
2
H
O
CO
2
Me
Jones
reagent
Acid-mediated
desilylation and
subsequent oxidation
TBS =
t
butyldimethylsilyl
Bn = benzyl
N
H
2
Cr
2
O
7
2-
Pyridinium dichromate
(PDC)
N
H
ClCrO
3
-
Pyridinium
chlorochromate (PCC)
S
Cl
R
1
OH
-HCl
R
1
O
S
H
H
NEt
3
R
1
O
S
H
R
1
O
H
Me
2
S +
! The Swern oxidation: (i) activation of DMSO
! Selectivity in oxidation of alcohols
! The Swern oxidation: (ii) activation of the alcohol
1. Effective for primary and secondary alcohols
2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt
This is an excellent method for the selective oxidation of primary alcohols to aldehydes
S
O
Cl
Cl
O
O
O
O
O
Cl S
Cl
-
S
Cl
C
O
O
+ CO +
DMSO Oxalyl chloride
-78C
DCM
Chlorosulfonium salt is effectively the oxidant - unstable above approx -60C
Chlorosulfonium
salt
alkoxysulfonium
ylide
aldehyde alkoxysulfonium
salt
primary alcohol
S
Cl
R
1
OH
-HCl
R
1
O
S
H
H
NEt
3
R
1
O
S
H
R
1
O
H
Me
2
S +
! The Swern oxidation: (i) activation of DMSO
! Selectivity in oxidation of alcohols
! The Swern oxidation: (ii) activation of the alcohol
1. Effective for primary and secondary alcohols
2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt
This is an excellent method for the selective oxidation of primary alcohols to aldehydes
S
O
Cl
Cl
O
O
O
O
O
Cl S
Cl
-
S
Cl
C
O
O
+ CO +
DMSO Oxalyl chloride
-78C
DCM
Chlorosulfonium salt is effectively the oxidant - unstable above approx -60C
Chlorosulfonium
salt
alkoxysulfonium
ylide
aldehyde alkoxysulfonium
salt
primary alcohol
! Revisit complex example: the order of addition is important
! Swern oxidation: methyl homosecodaphniphyllate
Key: never unmask aldehyde in the presence of reactive functional groups
OBn
H
HO
HO
OBn
H
O
O
(COCl)
2
, DMSO,
CH
2
Cl
2
-78C
OBn
H
O
O
S
S
then add
Et
3
N
OBn
H
HO
O
bis-alkoxysulfonium salt
mono-oxidation
[generates mono-aldehyde]
in situ
OBn
H
O
HO
OBn
H
O
O
further
oxidation
hemiacetal
formation
There is no control over which alcohol is oxidised first in the lower route.
! Parikh-Doering oxidation (SO
3
.pyridine is the DMSO activator)
! Alcohol oxidation: other DMSO-based reagents
Mechanisms are essentially the same as the Swern,
but with the electrophilic DMSO activator being SO
3
or DCC
! Pfitzer-Moffat oxidation (DCC is the DMSO activator)
OTBS
S
S
HO
HO
H
OTBS
S
S
HO
O
H
SO
3.
py, Et
3
N
CH
2
Cl
2
/DMSO, rt
Cl O
t
Bu
OH
DMSO, DCC
H
+
, pyridine
Cl O
t
Bu
O
SO
3
.pyr is a crystalline solid
Mild and scaleable oxidation
Selective for 1 alcohol ^ aldehyde
No diol cleavage
Possible side reactions: Pummerer
rearrangement, and acid-induced
problems for sensitive substrates
N
C
N
DCC = Dicylclohexylcarbodiimide
[the dicylohexylurea biproduct of this
reaction can be difficult to remove
from the reaction mixture]
! Hypervalent iodine oxidant: mild, reliable and works at RT (stylized mech.)
! Dess-Martin Periodinane (DMP)
Selective for oxidation of 1 alcohols to aldehydes with no overoxidation
! Examples (often used for complex, highly functionalized materials)
O
Me
I
HO
TBSO
Me
Me
Me
H H
O
Me
I
O
TBSO
Me
Me
Me
H H 1.5 eq DMP
DCM, RT
MeO
O
O
OH
MeO
O
O
O
DMP
RT
AcOH biproduct can be buffered for
very sensitve substrates
O
I
O
AcO OAc
OAc
R
1
R
2
HO
O
I
O
AcO
O
H
R
1 R
2
O
O
O
I
O
OAc
R
1
O
R
2
1.5 eq DMP
DCM, RT
! Mechanistically, the first step is ligand exchange so we would expect to be
able to kinetically discriminate between primary and secondary alcohols:
! Dess-Martin Periodinane (DMP)
Limitations: can cleave diols (like periodate, another hypervalent iodine oxidant)
HO
OMe TBSO OTBS
O
O
HO
OTBS
OTBS
O
OMe TBSO OTBS
O
O
HO
OTBS
OTBS
DMP
DCM, RT
! Allylic and benzylic alcohols oxidized faster (but can & will oxidize 2 alcohols)
O O
HO
OH
H
O O
HO
O
H
DMP
DCM, RT
1 alcohol oxidized preferentially;
2 alcohol left untouched
2 allylic alcohol
oxidized faster than
normal 2 alcohol
HO
R
1
Mn
O
O
O
Mn
O
OH
H
R
1
O
Mn
OH
OH
R
1
O
R
1 Mn
OH
OH
Manganate ester allylic/benzylic
alcohol
aldehyde/ketone
! MnO
2
: a selective oxidant for allylic and benzylic alcohols
! Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols)
! Selectivity is probably a consequence of a radical mechanism
OH
MnO
2
DCM
OH
O
OH
Allylic alcohol oxidized selectively
Mn(IV) Mn(IV) Mn(III) Mn(II)
Hydrogen abstraction is faster for allylic/benzylic alcohols
(the radical that is produced is delocalized and hence more stable)
! MnO
2
: a selective oxidant for allylic and benzylic alcohols
MnO
2
is a heterogeneous oxidant: workup is generally just filtration
! Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols)
! The aldehyde products can be used in-situ with other reagents (MnO
2
is v. mild)
MnO
2
CH
2
Cl
2
Bu
3
Sn OH Bu
3
Sn
O
Mild conditions; can retain vinyl stannane group
aldehyde formed in-situ, condenses with amine
to form intermediate imine
NaBH
4
reduction of imine faster in polar
protic solvent (MeOH)
Oxidant (MnO
2
) compatible with reductant (NaBH
4
) in same vessel
MnO
2
, CH
2
Cl
2
NaBH
4
, 4 sieves
amine
then methanol
OH N N [red]
Ru
O O
O O
N
Pr Pr
Pr Pr
Ru
O O
O
R
1
R
2
HO
R
1
R
2
O
N
O
O
N
O
! Ru(VII) with organic-soluble counterion is a selective oxidant and can be
used catalytically with a co-oxidant (mechanistically complex!)
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate TPAP
Selective for oxidation of 1 alcohols to aldehydes with no overoxidation
Ru(VII)
Ru(V)
1/2 alcohol
Aldehyde/ketone
Co-oxidant
NMO
Ru(VI): active Ru(IV): inactive
Ru
O
O
Ru
O
disproportionation
O
O
+2e
! Examples (4A sieves remove water to prevent hydration and overoxidation)
Limitations: Can cleave diols (like high valent Manganese and periodate)
O O
OTBS
MeO
MeO H MeO
H H
HO
TBSO O
O
O O
OTBS
MeO
MeO H MeO
H H
O
TBSO O
O
TPAP (10 mol%)
NMO, DCM
4 sieves
! Mechanism: consistent with ruthenate ester (though complex & unproven!)
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate TPAP
R
1
Ru
O O
R
1
R
2
O
Ru
O
O
H
R
2
O O
OH
R
1
R
2
O
Ru
O O
OH
O
OH
Ruthenate ester
Ru(VII) Ru(VII)
Ru(V)
1/2 alcohol aldehyde/ketone
! Can use in conjunction with the Wittig reaction for reactive aldehydes
! Steric selectivity can be exploited: generation of lactones (compare Swern)
OH
O
TPAP (10%)
NMO
DCM
4 sieves
OH
OH
O
O
O
O
O
O
O
OH
[ox]
TPAP will also oxidize sulfur but not other heteroatoms
Lactone Lactol
readily oxidized
1 alcohol
TPAP (10%), NMO
DCM, 4 sieves
O OH
O
Ph
3
P CO
2
Et
O
O
CO
2
Et
Stabilized ylide; E/Z >20:1
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate TPAP
! Thermodynamics in Oxidation: the Oppenauer reaction
Generally superceded by other oxidants, but inexpensive and non-toxic.
! The reverse of the Meerwin-Pondorrf-Verley reduction (see Dr E. Anderson course, HT 2011)
! Very mild, uses non-toxic reagents and can be employed on a large scale
O
M
O
H
R
1
R
3
R
4
R
2
L
L
R
1
R
2
O
R
3
R
4
OH
H
Metal
Alkoxide
R
1
R
2
OH
R
3
R
4
O
H
Oxidant Reduced Oxidized
M = Al, Zr, B, Ru,
Zr(O
t
Bu)
4
OH
Cl
3
C
O
H
O
NMe
O
HO
MeO
NMe
O
O
MeO
O
Al(O
i
Pr)
3
! Oxoammonium-mediated oxidations
! Most common reagent is TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy
N
O
TEMPO is used catalytically with a co-oxidant
TEMPO
Oxoammonium
1/2 alcohol
Aldehyde/ketone
Co-oxidant
TEMPO
Actual oxidizing agent
N
OH
N
O
R
1
R
2
HO
R
1
R
2
O
NaOCl
I
AcO OAc
'BAIB'
or
Cl
2
I
or
N
O
disproportionation
! Oxoammonium-mediated oxidations
Generally: mild, functional group tolerant reagent
! Mechanism:
! Examples:
Actual oxidant
oxoammonium
1/2 alcohol
aldehyde
or ketone
PMBO OH
MeO
TEMPO
NaOCl
KHCO
3
PMBO
O
PMB =
TEMPO
BAIB
N
OMe
TBSO O
HO
N
OMe
TBSO O
O
N
O
R
1
R
2
HO
N
O
H
R
2
R
1
O
N
OH
R
1
R
2
O
reoxidation
! Functional groups have different kinds of reactivity
O OH O
Pd/C
H
2
NaBH
4
ketone-
electrophilic
alkene- not
electrophilic
use catalytic
hydrogenation
use nucleophilic
reagent
! Selectivity in reduction: hydride reducing agents
! For chemoselective and regioselective hydride reduction - which reagent?
O O
EtO
OH O
EtO
O
HO
1. NaOH
2. BH
3
NaBH
4
CeCl
3
OH
HO
LiAlH
4
Important to use the correct hydride for the correct transformation!
!
R' H
NHR
R H
O
R R'
O
R OR'
O
R NR'
2
O
R OH
O
imine aldehyde ketone ester amide acid
R H
O
R H
O
R H
O
R' NHR R OH R R' R OH
R NR'
2 R OH
OH
amine 1 alcohol 2 alcohol 1 alcohol amine 1 alcohol
NaBH
3
CN
NaBH
4
LiBH
4
BH
3
!
LiAlH
4
"
!
! !
! ! !
! ! ! !
! !
" " "
" "
" "
! !
!
! ! !
!
Reduced
Not usually reduced
Slow
DIBALH
(low temp)
LiAlH
4
(low temp)
via Acid
Chloride
! Selectivity: hydride reducing agents (not ALWAYS reliable..)
tetrahedral
intermediate
R OR
O
R
2
Al H
R OR
O
Al
H
R R
R OR
H R
2
AlO
R OR
H HO
R H
O
H , H
2
O
unstable
hemiacetal
H , H
2
O
ester reduced to
aldehyde with DIBALH
at low temperature
! DIBALH (Di-Iso-Butyl Aluminium Hydride)
! Selectivity in reduction: hydride reducing agents
Exists as H-bridged
dimer but reacts as
monomer.
Al has empty p-orbital
in monomer so is
electrophilic.
Al
H
Al
H
Al H
! DIBALH becomes a good reducing agent after reacting with a nucleophile
DIBALH reduces most
nucleophilic C=O group
stable at low
temperatures
destroys any excess DIBALH
! DIBALH is a powerful and less selective reagent at higher temperatures
! Selectivity in reduction: hydride reducing agents
! Often used at RT for reduction of esters to alcohols
N
H
OEt
O
Ph
t
BuO
O
N
H
OH
Ph
t
BuO
O
DIBALH
BF
3.
OEt
2
CH
2
Cl
2
, RT
MeO
O
O
OMe
OTBS
MeO
O
OH
OTBS
DIBALH
CH
2
Cl
2
, RT Selective 1,2-
reduction
Complete reduction of
ester to 1 alcohol
with excess DIBALH
at RT
tetrahedral
intermediate
R OR
O
R
2
Al H
R OR
O
Al
H
R R
R OR
H
R
2
AlO
R
O
H
aldehyde - much more
reactive than ester SM
R
OH
H
at RT this intermediate
is NOT stable
rapid reduction
to alcohol
! Application: the reduction of lactones
! Stopping reactions half way: reduction
The reactive aldehyde is never unmasked in the presence of reactive functionality
the tetrahedral intermediate is stable under the reaction conditions
! Is this approach a solution to a common problem?
more electrophilic
note regioselectivity too: direct rather than conjugate addition
less electrophilic
R
1
OR
O
R
1
R
2
O
R
1
R
2
OH
R
2
OMe
O O OH
or R
2
Li or R
2
Li
ester ketone product formed
R
2
MgBr R
2
MgBr
BuLi BuLi
O
O
O
OAlR
2
H
O
OH
H
DIBALH
Ph
3
P R
H , H
2
O
stable cyclic
hemiacetal
HO
R
2 equivalents
R
1
Cl
O
Me
HN
OMe
R
1
N
O
OMe
Me
R
2
Li
R
1
N
OMe
Me
R
2
O
Li
R
1
N
OMe
Me
R
2
O
Li
R
1
N
OMe
Me
a Weinreb amide
R
2
OH
R
1
R
2
O
H
2
O
H
R
Li
H NMe
2
O
H NMe
2
R OLi
H NMe
2
R O
H
H
H R
O
DMF
H
H
2
O
! Solution: use amides as electrophiles
! Stopping reactions half way: Weinreb amides
stable under
reaction conditions
As seen in
ortho-lithiation
! A Weinreb amide is a better solution to this problem
tetrahedral intermediate
stabilised by coordination
decomposes during
acidic work-up
R-Li R-MgX
RO
OLi
R
LiN
Li
DIBALH LiAlH
4
Acceptable
nucleophiles:
N
Me
OMe
O
O
t
Bu
OLi
THF, -78C
CO
2
t
Bu
NMe
O Li
O
O
O
t
Bu
O
83 % yield
! Grignard addition
! Examples of the use of Weinreb amides
! DIBALH reduction
N
OMe
Me
Me
Me OMe Me
TBSO
Me
O
OMe
Me
OMe
O
2
N
OMe
H
OMe
Me
Me
Me OMe Me
TBSO
Me
O
OMe
O
2
N
OMe
DIBALH
THF, -78C
95% yield
! Enolate additions
N
O
N Me
O
OMe
OTBS
Ar
N
O
Me
O OTBS
Ar
MeMgBr
THF, 0C
99% yield
N
O
Me
OTBS
Ar
Me
O
Mg
O
N
"-keto ester:
C-acylation requires control
tetrahedral intermediate
stabilized by coordination
tetrahedral intermediate
stabilized by coordination
! The problem: acylation of ketones can be difficult to control
! Stopping reactions half way: Acylation at Carbon
R
1
OR
O
R
1
O
ester ketone
R
2
O
R
2
O
R
2
O
further
reaction?
more electrophilic less electrophilic
! Solution: Employ kinetic or thermodynamic control in Claisen condensation
R
1
OR
2
O
OR
2
O
R
1
OR
2
O
OR
2
O
R
1
O
R
1
R
1
H
OR
2
O
R
1
O
R
1
R
2
O R
2
O
electrophilic ketone
acylation
at carbon
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
stable, non-electrophilic
enolate - the product under
the reaction conditions
! Intramolecular (Dieckmann) condensation can offer a solution to C-acylation
! Thermodynamic control
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
Irreversible
alkylation
! Regioselectivity through thermodynamic control
EtO EtO
O
EtO OEt
O
O
CO
2
Et
H
EtO OEt
O
EtO
2
C
O
Cannot form a
stable enolate
Can form a
stable enolate
CO
2
Et
O
CO
2
Et
O
CO
2
Et
O
H Me
O
OEt
CO
2
Et
EtO EtO MeI
! Enolate stability can control regiochemistry of C-acylation
! Acylation at Carbon - Kinetic vs thermodynamic
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
Kinetic product
Thermodynamic product
! With reversible enolization conditions we get equilibration between all species
O O
O
CO
2
Me
O
CO
2
Me
O
CO
2
Me
O
CO
2
Me
H
This enolate destabilized by
interaction with aromatic
C-H bond - precludes
planarity
No such destabilizing
interaction - more stable
enolate
O O O
CO
2
Me
CO
2
Me
NC OMe
O
LDA, -78C
MeO OMe
O
NaH, 0C
! Enolate stability can control regiochemistry of C-acylation
! Acylation at Carbon - Kinetic vs thermodynamic
Kinetic product
Thermodynamic product
! Stabilizing the intermediate precludes proton transfer under reaction conditions
O O O
CO
2
Me
CO
2
Me
NC OMe
O
LDA, -78C
MeO OMe
O
NaH, 0C
NC OMe
O
R
1
O
R
2
R
1
OLi
R
2
LDA
-78C
fast
R
2
OMe
O
R
1
O
CN
Li
slow
R
2
OMe
O O
R
1
! Example:
NC OMe
O
LDA, -78C
Me Me
O
Me
O O
OMe
Notes: pKa MeOH = 16, pKa HCN = 9.5
R
1
N
R
2
O
R
3
Al
H
H
H
H
R
1
N
R
2
O
R
3
H
Li
R
1
N
R
2
O
R
3
H
Al
H
H H
R
1
N
R
2
R
3
H
R
1
N
R
2
R
3
H
Al
H
H
H
H H
! Specific reducing agents: Lithium Aluminium Hydride LiAlH
4
! Powerful and (somewhat) non-selective reducing agent: will reduce
aldehydes, ketones, esters and amides (anomalous: see mechanism below)
Al is Lewis
acidic
Iminium much
more reactive
All 4 hydrides
active in principle
Retain C-N bond (compare
with ester reduction)
! Examples:
O
O
MeO
H
N
O
Me
H
O
OH
MeO
H
N Me
H
LiAlH
4
THF
H H
O
O O
Me
Me
HO
O HO
Me
Me
LiAlH
4
THF
Reduces amide and leads to 1,2-reduction of
!,"-unsaturated ketone (hard nucleophile)
Lactone (ester) reduction leads to diol
production (note cleavage of C-O bond)
[AlH
4
]
-

or [AlH
(4-n)
OR
n
]
-
Li counterion important
(reaction ineffective without it)
! Specific reducing agents: Lithium Borohydride LiBH
4
! Typically used for the selective reduction of esters in the presence of
amides, nitriles and carboxylic acids (will also reduce aldehydes and ketones)
! Examples:
H
N
N
H
OTBS
O
O CO
2
Me
O
2
N
F
H
N
N
H
OTBS
O
O
O
2
N
F
LiBH
4
THF
OH
MeO
2
C CO
2
H
HO CH
3
LiBH
4
THF
HOH
2
C CO
2
H
HO CH
3
LiBH
4
THF
N
CO
2
Me
CN
O
N
CN
O
OH
Ester is reduced (with cleavage of the C-O
alkyl bond) but amide is left untouched
Ester is reduced (with cleavage of the C-O
alkyl bond) but acid is left untouched
Selective ester reduction; nitrile and
amide are left untouched
Can be made in situ: LiI or LiBr + NaBH
4
R
1
R
2
O
B
H
H
H
H
R
1
R
2
O
H
H
B
H
H
OR
H
H
OMe
! Specific reducing agents: Sodium Borohydride NaBH
4
! Less reactive (than LiAlH
4
& LiBH
4
), more selective. Generally used in MeOH
or EtOH & will not usually reduce esters, epoxides, lactones, nitriles. Mech:
! Examples:
NaBH
4
slowly reacts with protic
solvents (or alcohol products) to
generate alkoxy borohydrides
All 4 hydrides
active in principle
Na
+
counterion less
important than solvent
1. NaBH
4
,
MeOH
2. 6M HCl
OMe O
NEt
2
O
H
OMe
O
O
ketone is reduced but ester and vinyl iodide
are left untouched
aldehyde is reduced but amide left
untouched (by reduction, anyway)
O
O
I
O
O
O
O
I
OH
O
NaBH
4
MeOH
! The Luche reduction: NaBH
4
+ CeCl
3
.7H
2
O
! NaBH
4
is not selective for 1,2 vs 1,4 reduction: CeCl
3
increases selectivity
! Examples:
1,2-reduction favored by addition of Ce salt
CeCl
3
accelerates rate of reaction of protic solvent
with NaBH
4
to generate alkoxyborohydrides
NaBH
[4-n]
OMe
n
These are harder reducing agents and favour attack
at the hard rather than the soft center
O OH OH
Reductant
MeOH
NaBH
4
51% 49%
NaBH
4
, CeCl
3
99% trace
Exclusive 1,2-reduction
Exclusive 1,2-reduction
No ester reduction
N
3
CO
2
Me
O
N
3
CO
2
Me
OH
NaBH
4
CeCl
3
.7H
2
O
MeOH
NaBH
4
CeCl
3
.7H
2
O
MeOH
O
O
H
O OBn
O
OH
H
O OBn
! Other modified Borohydrides
! NaBH
3
CN and NaBH(OAc)
3
: reagents of choice for reductive amination
! Super-Hydride
TM:
alkyl groups make it the most nucleophilic hydride source
NaBH
3
CN
CH
2
O
pH 5
N
O
H
Me
Ph
N
O
H
Me
Ph
H
Me
Reduces intermediate imine/iminium NOT
aldehyde: selective reductive amination
Reduces intermediate imine/iminium NOT aldehyde. SnCl
2
Lewis acid accelerates iminium formation
Ph
HO
Ph
MsO
Ph
H
MsCl, Et
3
N
LiEt
3
BH
THF
Electron donating groups
increase hydride donor
ability of B-H bond
The most nucleophilic hydride: especially effective for
S
N
2 type reactions on activated leaving groups
challenging S
N
2 (neopentyl)
N
H
O
OTBS
H
R
O
Me AcO
NaBH(OAc)
3
SnCl
2
N O
OTBS
H
R
Me AcO
! Specific reducing agents: Borane BH
3
! Reagent for rapid reduction of acids (compare LiAlH
4
); idealized mechanism:
! Examples
B is Lewis
acidic
B is Lewis
acidic
OR
2
group could be
THF or substrate
Only 1 eq. BH
3
per
acid required
Selective acid reduction - no
reduction of lactone
Selective acid reduction
No 1,4-reduction; no ester reduction
R
1
OH
O
B
H
H H
R
1
O
O
B
H
H H
H
R
1
O
O
B
H
H
-H
2
THF
OR
2
R
1
O
O
B
H
H OR
2
R
1
O
B
H
OR
2 O
H
R
1
O
H R
1
O
H
B
H
HO OR
B
OR
2
HO
H
R
1
OH
H
H
H
+
workup
O
O
Br
H Me
CO
2
H
O
O
Br
H Me
OH
BH
3
.THF
HO
2
C
CO
2
Et
BH
3
.THF
CO
2
Et HO
! Chemoselectivity with hydrides: recap
R' H
NHR
R H
O
R R'
O
R OR'
O
R NR'
2
O
R OH
O
imine aldehyde ketone ester amide acid
R' NHR R OH R R' R OH
R NR'
2 R OH
OH
amine 1 alcohol 2 alcohol 1 alcohol amine 1 alcohol
NaBH
3
CN
NaBH
4
LiBH
4
BH
3
LiAlH
4
!
! !
! ! !
! ! ! !
! !
" " "
" "
" "
! !
!
! ! !
!
What about stereoselectivity in reduction?
! Diastereoselectivity with hydrides: 1,2-stereoinduction
! Felkin-Anh model (see Dr E. Anderson course HT 2011)
! Felkin Polar model
! Felkin Chelation model
Ph
O
SMe
Ph
Me
OH
Me
LiBH(s-Bu)
3
THF
Me
Ph
O
OMe
Me
Ph
OMe
Zn(BH
4
)
2
THF
OH
Ph
Me
O
Me
Ph
Me
OH
Me
LiBH(s-Bu)
3
THF
1. Electronegative group is
treated as large
2. #* C=O overlap with $*
C-S (lower LUMO)
3. Forming C-Nu bond
stabilized by C-X $*
1. Reactive conformation
2. Brgi-Dunitz trajectory
3. Attack away from R
L
4. TS is SM-like
1. Lewis acid metal
2. electronegative group
coordinates to metal
3. Controls reactive
conformation
H
MeO
Me
O
Ph
H
B
R
R
R
Zn
2+
H
i
Pr
MeS
O
Me
H
B
R
R
R
H
Me
Ph
O
Me H
B
R
R
R
Felkin product
anti-Felkin product
Felkin product
! Diastereoselectivity with hydrides: 1,3-stereoinduction
! 1,3 polyols are components of many natural products
O
O
Me
OH
OH OH
Me
OH OH OH
HO
1,3-syn 1,3-anti
OH OH OH OH
! A disconnection approach indicates how to assemble the 1,3-arrangement
(+)-Roxaticin
OH OH
R
1
R
2
R
2
R
2
OH OH OH O
R
1
R
2
FGI
[red]
FGI
[red]
1,3-syn 1,3-anti
Can we use the stereochemistry of
this product to direct hydride
reduction to afford either the syn- or
anti- product?
! Diastereoselectivity with hydrides: 1,3-stereoinduction
! 1,3-syn diols may be generated by using a Lewis acid to favor intermolecular
hydride delivery from the least hindered face:
OH O
R
1
R
2
B
O
O
R
1
R
R
R
2
R
3
B, MeOH
NaBH
4
H
-
OH OH
R
1
R
2
! 1,3-anti diols may be generated by using intramolecular delivery of the
hydride nucleophile
1,3-syn Boron is
Lewis acidic
Chair-like TS
axial attack of hydride
OH O
R
1
R
2
OH OH
R
1
R
2
H
B
O
H
R
1
H
H
OAc
OAc
O
H
R
2
Me
4
NBH(OAc)
3
Boron is
Lewis acidic
Chair-like TS
put substituents pseudo-equatorial
Intramolecular delivery
1,3-anti
! Diastereoselectivity with hydrides
! Size matters: addition to cyclohexanones (see Dr E. Anderson course HT 2011)
LiAlH
4
Small H
-
9:1, axial/equat. attack
Na(s-Bu)
3
BH
Big H
-
96:4, equat./axial attack
So equatorial attack appears to be favoured, as it does not require the hydride to approach
across the ring (where 1,3-diaxial interactions hinder trajectory)
! Why is axial attack then favoured for small hydrides (nucleophiles)?
O
H
H
axial
equatorial
Equatorial: O moves towards
C-H, leading to higher
torsional strain in the TS
Axial: O moves away from
C-H, leading to lower
torsional strain in the TS
H
H
O
Large
Hydride
Small
Hydride
'Axial
attack'
'Equatorial
attack'
H
-
H
-
H
H
H
H
OH
H
H
OH
N
NH
2
O
H H
R
*
N HN
H
O
O
O H
H N
N
NH
H
H
! Enantioselectivity with hydrides I
! How does Nature perform reductions?
Histidine
N
NH
2
O
H H
R
*
N
NH
2
O
R
*
lactate
dehydrogenase
O
CO
2
CO
2
OH H
Asparagine
NADH NAD
NADH
Enzyme holds groups in
appropriate position for
reactivity (to stabilize TS)
and provide selectivity
! We can mimic this in the lab by using Mg
2+
to control conformation
NADH-like
lactate-
like
S-(+)-lactate
Mg activates and
controls conformation
Aromatic biproduct
(a pyridinium salt)
Single enantiomer
produced
MeO
O
Ph
OH
(S)-(+)-enantiomer
N
O
O
Ph
O
Me
H
Ph
N
OH
O
Ph
O
Ph
H
Me
N
Me H
Ph
O
O
Ph
O
Mg
2+
Mg
2+
MeO
-
! Enantioselectivity with hydrides II
! We can put the chiral group on the reagent too (chiral NaBH
4
)
CBS reagent
Chiral reducing agent
Made from Proline
N
B O
H
H
3
B
Ph
Ph
R
Ph
Ph
Ph Me
O
Ph Me
OH
N
B O
H
H
3
B
Ph
Ph
BH
3
(R)-alcohol,
97% ee
10 mol% cat.
R
N
B
O
R
O
Me
Ph
B
H
H
H
Trivalent boron is lewis acidic
Hydride delivered from 'top' face
Overall: boat-like arrangement
BH
3
used to regenerate active material
! A highly effective reagent for enantioselective reduction of ketones
N
B O
H
Ph
Ph
R
Ph
Cl
O
(1 mol%)
BH
3
, THF
Ph
Cl
OH
98:2 ratio of
enantiomers
TBSO
Me
O
Me
TBSO
Me
OH
Me
N
B O
H
Ph
Ph
Bu
(1 mol%)
BH
3
, THF
97:3 ratio of
diastereoisomers
! Reduction of alkynes (recap of 1st year material)
! Overall cis- addition of hydrogen across the alkyne: hydrogenation
! Overall trans- addition of hydrogen across the alkyne: dissolving metal
Isolated alkenes are not usually
reduced under these conditions
Anion adopts trans-
configuration
R
1
R
2
R
1
R
2
H
2
(g)
Lindlar
catalyst
cis alkene
H H
hydrogen on
catalyst surface
H H
R
1
R
2
Na
NH
3
(l)
R
1
R
2
N
H
H H
R
1
R
2
H
NH
3
(l)
R
1
R
2
H
NH
3
(l)
R
1
R
2
H
H
Na
NH
3
(l)
LUMO
C C
!*
! Dissolving metal reductions: The Birch reduction
! The Birch reduction can be used to partially reduce aromatic rings
H H
H H
Na, NH
3
(l), EtOH
Kinetic product is non-
conjugated diene
! The regiochemistry of the reduction depends on substitution
A range of metals can be
used: Li, Na, K (sometimes
even Ca and Mg)
Na, NH
3
(l), EtOH
OMe OMe
H
H
H
H
Na, NH
3
(l), EtOH
CO
2
H
H H
H CO
2
H
Electron-donating groups (OR,
NR
2
, alkyl) give rise to this
orientation of reduction
Electron-withdrawing groups (CO
2
H,
CO
2
R, COR, CONR
2
, CN, Ar) give rise
to this orientation of reduction
! Dissolving metal reductions: The Birch reduction
! Mechanism: reduction of arenes bearing EDG (OR, NR
2
, alkyl)
Addition of electron into
benzene LUMO
Li (or Na)
NH
3
(l)
Li
+
e [NH
3
]
n
A dark blue solution of solvated electrons. This is
the actual reducing agent in the Birch reduction
Delocalized radical anion
Undergoes ortho-
protonation (probably)
Undergoes para-
protonation
1. Reduction of alkyl benzenes and aryl ethers requires a proton
source stronger than ammonia (usually an alcohol).
2. First protonation occurs ortho- as this is the site of highest
charge (and gives the most stable intermediate)
3. Second protonation occurs para- to give the non conjugated
product: kinetic control and a consequence of the pentadienyl
anion HOMO having the largest coefficient in this position
Isolated C=C are not
usually reduced
RDS
Na, NH
3
(l)
EtOH
"e "
OMe OMe OMe
H OEt
OMe
H
H
H
Na, NH
3
(l)
EtOH
"e "
OMe
H
H
H H H
OMe
H
H
H OEt
H
H
! Dissolving metal reductions: The Birch reduction
! Mechanism: reduction of arenes bearing EWG (aryl, carbonyl, acid, nitrile)
Addition of electron into
benzene LUMO
Undergoes para-
protonation
Undergoes ipso-
protonation
1. Carboxylate will be deprotonated under reaction conditions
2. First protonation in para- position: site of highest charge (and
most stable intermediate)
3. Kinetic and irreversible protonation to give non-conjugated
product.
! Examples:
Na, NH
3
(l)
EtOH
Me OMe Me OMe
Na, NH
3
(l)
EtOH
Me CO
2
H Me CO
2
H
Isolated C=C are not
usually reduced
Both EDG: direct
reduction to same
orientation
One EWG and one
EDG: both direct to
same orientation
Na, NH
3
(l)
EtOH
"e "
CO
2
H CO
2
CO
2
H OEt Na, NH
3
(l)
EtOH
"e "
H OEt
H
H H
CO
2
CO
2
H H H H
H CO
2
H
! Dissolving metal reductions: The Birch reduction
! The proton source is important
non-conjugated
diene (with EtOH)
more reduction
without EtOH
! NH
3
functions as a proton source (to make NH
2
-
) if there is nothing better
normal non-
conjugated product
thermodynamic
conjugated product
conjugated product:
further reduction
Na, NH
3
(l)
EtOH
OMe OMe
H
H
H
H
Na, NH
3
(l)
OMe
Na, NH
3
(l)
OMe
OMe
H
H
H
H NH
2
OMe
H
H
H
H
NH
2
-
OMe OMe
NH
3
functions as
proton donor
NH
2
-
strong base
can isomerize
Some reductions do not proceed without the proton source.
Applications of the Birch reduction
Reductions of conjugated alkenes
Conjugated alkene is
reduced more rapidly than
electron-rich arene
MeO
H
H
3
C
O O
MeO
H
H
3
C
O O
K, NH
3
THF, -70C
H
H
Reductive alkylation: alkylation of the pentadienyl anion intermediate
OMe
CO
2
t
Bu
OMe
1. K, NH
3
1eq.
t
BuOH
2.
i
PrI
CO
2
t
Bu
i
Pr
One equivalent of
t
BuOH to permit
first para- protonation, then kinetic
alkylation of pentadienyl anion
CN
OMe
CN
OMe
Cl
1. Li, NH
3
1eq.
t
BuOH
2.
Br Cl
Regiochemistry of reduction a consequence
of substitution; note alkylation via
displacement of best leaving group